In order to deliver drugs which may include medicines, vitamins and other substances directly to the intestines by oral means, such active substances are usually coated with gelatin based materials such as capsules or caplets. This is due to the fact that if such substances are not coated with a protective coating, such substances would be broken down in the highly acidic environment of the stomach.
Capsules are usually made in rigid or soft form wherein powders or granules of a drug or other active ingredient are enclosed in a rigid gelatin shell or in soft gelatin shell which soft shell may also contain glycerol as well as gelatin to maintain plasticity of the outer shell. Powder semi-solids or liquids that do not soften or dissolve the gelatin shell can be enclosed. Powder and semi-solids can be encapsulated in a two part shell i.e. cap and body whereas liquids may be encapsulated in a capsule that is formed, fitted and heat sealed all in one operation using especially designed apparatus.
In addition to inert polymers that control drug diffusion, polymers can be designed to dissolve, swell, or degrade in a controlled manner, thereby releasing the incorporated drug. It is, however, necessary that the polymer be transformed into a water-soluble product that evokes no limiting toxic response if the spent product is not to be reclaimed. The drug is locked into a polymer matrix (i.e. a drug reservoir) before its transformation. The surface area of the polymer-drug mass, the drug concentration and solubility characteristics, and the rate of polymer transformation affect the rate at which the drug is delivered. The polymer structure undergoes a phase change during which it or its by-products are removed or eliminated from the body, either during drug release or when most of the drug is deployed.
The polymers investigated for such systems include polyesters, polyorthoesters, polyacids, hydrogels, celluloses, polypeptides, polyaminotriazoles, and albumin beads. Therapeutic agents investigated for delivery from polymeric matrices include narcotic antagonists (naloxone), steroids, antimalarials, insulin, enzymes, antibacterials, ophthalmic agents, vitamins and anticarcinogens.
Encapsulation with liposomes promotes the passage of drugs across cell-membrane barriers, prolongs plasma lifetime of drugs with short biological half-lives, and directs drug disposition. The aqueous compartments bounded by bimolecular lipid layers carry the drug-containing platform closer to the target site, thus providing higher concentrations than the usual systemic therapy. The quantity of the drug or agent administered can, therefore, be reduced considerably.
Active ingredients which are required to be released in different parts of the alimentary tract may be coated or packaged in materials which react differently with body fluids having varying pH values in different parts of the alimentary tract.
Coatings which resist the action of gastric acids but dissolve under the less acidic conditions in the duodenum and intestines are generically known as enteric coatings and are applied to capsules as well as tablets.
Although enteric capsules have been known since the end of the 19th century their development has not paralleled that of enteric-coated tablets. This has been mainly due to the difficulties in making enteric capsules completely resistant to gastric acids.
Gelatin-based capsules, however, may be made acid resistant by treating them with formaldehyde. This process has a disadvantage in that the chemical cross linkage changes to the gelatin as a result of the formaldehyde treatment can continue during a storage period resulting in an undesirable hardening of the capsules.
Furthermore, trace amounts of formaldehyde in foods and pharmaceuticals because of the toxic properties of this substance also raises problems with food and drug administration authorities.
Gelatin capsules may also be coated with a solution of cellacephate, as described in U.S. Pat. Nos. 2,491,475 and 2,575,789. Cellacephate is a composition consisting of a mixture of gelatin and an alkali metal salt of a partial ester of a polycarboxylic acid and a suitable cellulose ether. For example, a solution of sodium carbonate in which cellacephate was dissolved was mixed with gelatin. Capsules were then made from this mixture. U.S. Pat. No. 2,718,667 refers to enteric capsules prepared solely from an alkali metal salt of cellacephate.
Capsules produced by cellacephate/gelatin mixtures however have the unfortunate disadvantage of being somewhat unstable on storage because of the decomposition of the cellacephate which liberates acetic acid. This results in a brittle capsule which is less soluble in the intestines and markedly reduces product yield.
Derivatives of cellulose with enteric properties have also been developed. An example of this is U.S. Pat. No. 3,826,666 which refers to a preparation of enteric capsules from a mixture of gelatin and the alkali metal salt of hypromellose phthalate. This resulted in an effective yield of capsules of between 80% and 90%. Further, soft single piece capsules with an improved film strength have also been produced by a mixture of cellacephate and hypromellose phthalate with gelatin and the addition of casein and latex.
Enteric capsules produced from polymers not based on cellulose have also been developed. For example, JP 7310522 refers to a capsule prepared from a mixture of gelatin and acrylic copolymers. Commercial gelatin-based encapsulation of medicinal substances are disclosed in, for example,
(i) HUT853800-A, which refers to capsules formed from an emulsion containing surfactant, antioxidant and an aqueous solution of alkali metal alginate; PA1 (ii) U.S. Pat. No. 5,362,564, which refers to a seamless capsule containing a C.sub.2 -C.sub.6 fatty acid ester of sucrose sandwiched between hydrophobic layers and a coating film formed from a ester soluble polyhydric alcohol; PA1 (iii) JO4027352-A, which refers to an enteric soft capsule obtained from gelatin, a plasticiser film base and water-soluble polysaccharide cross-linked by calcium ions; PA1 (iv) U.S. Pat. No. 5,204,111, which refers to a capsule containing a hydrophobic substance, an isobutylene viscous oil and a polyvalent alcohol film coating; PA1 (v) U.S. Pat. No. 5,330,835, which refers to an alginate capsule formed from addition of an alginate solution to a polyvalent metal salt solution; and PA1 (vi) JP59036540-A, which refers to microcapsules formed from gelatin and gum arabic, sodium alginate or carrageenan wherein the microcapsules are coated with flour, starch, powdered fat, cellulose protein, inorganic salt, organic acid salt, amino acid and sugar. PA1 (i) application of preservative to the seaweed or kelp which may include granular salt in the case of wakame or ash in the case of konbu; PA1 (ii) washing of the seaweed or kelp to remove the preservative and other foreign matter; PA1 (iii) immersion of the seaweed or kelp in water to allow absorption of water or physiological salt solution; PA1 (iv) removal of the seaweed or kelp from the water and placing of pieces thereof on a flat surface; PA1 (v) covering of the seaweed or kelp with absorbent or blotting material to remove excess water in the case of wakame or alternatively with a non-blotting material in the case of konbu; and PA1 (vi) compressing the seaweed or kelp into a flexible film. PA1 (i) a base member having a concave surface; PA1 (ii) a roller member attached to the base member and capable of reciprocatable movement thereto; and PA1 (iii) a flexible belt rigidly attached to opposed ends of the base member in such a manner that the flexible belt is slackly supported on the concave surface and interposed between the roller member and the concave surface;
In all the above mentioned prior art specifications relating to capsules, survival of the capsule in the digestive environment of the stomach is primarily a function of both the thickness and the resistance to gastric acids of the encapsulating material. However, such capsules required the employment of complex chemicals such as polymers such as those described above and thus the production of such capsules was expensive. Such expense was often exacerbated when it was necessary to also employ special additives such as agar, glycerine, pectin and various water soluble alcohols.
Other substances which have been used for formation of capsules include sucrose, starch, talcum powder, kanzo powder (liquorice powder), rubber, grape sugar, crystalline cellulose, lactose titanium dioxide, calcium carbonate, ammonium phthalate, cellulose and other associated cellulose derivatives, sorbitol, juran gum and polyvinyl alcohol.
Another major disadvantage of the manufacture of capsules was that such manufacture necessitated the use of expensive apparatus especially adapted for this purpose.
Another major disadvantage of the prior art capsules was that the above materials had a tendency to break down in the stomach and thus the solution of overcoming this problem was to increase the thickness of the capsule which, however, could not be universally applied in operation.